12 December 2006. Some people may have no rhythm, but they do have synchrony, at least at the cellular level. Without it the heart would be a wriggling, useless mass and the capability of cerebral cortex, with millions of neurons firing in sophisticated unison, would be compromised. Though neuronal synchrony is not well understood, there are indications that it is crucial for normal brain function and behavior. In particular, recent evidence suggests that rhythmic disturbance among specific groups of neurons in the cerebral cortex may be associated with symptoms of schizophrenia. That view is supported by a recent study from Cameron Carter of the University of California, Davis, and collaborators at the University of Pittsburgh. The findings, reported in this week’s early online edition of PNAS, suggest that poor synchrony among neurons that generate specific brain oscillations called gamma waves is associated with altered cognitive control in schizophrenia patients.

Impaired cognition is a key aspect of schizophrenia and is thought to be a greater predictor of the inability to function on a daily level than are the more obvious positive symptoms, such as psychosis and delusions. Current antipsychotic drugs are of little help with cognitive problems, and some may even make matters worse. Cognitive deficits have been traced to alterations in the dorsolateral prefrontal cortex (DLPFC). Though the precise physiological impairments that lead to DLPFC problems are unclear, MRI studies have shown less activity in this region of the brain in schizophrenics, an indication that neurons may not be working at maximum capacity. In addition, postmortem analysis of brain tissue has shown that there may be compromised neurotransmission in a specific group of DLPFC inhibitory neurons called chandelier cells (see Lewis et al., 2005), whose sole job is to innervate and modulate pyramidal neurons, the major excitatory neurons of the cortex and the ones that give rise to measurable oscillations in the gamma band range (30-80 Hertz). “What our study does is tie these observations together. It suggests that what is driving the disabling cognitive deficits in schizophrenia is the inability to mount oscillations in the gamma frequencies in the prefrontal cortex, and it connects the behavioral and neuroimaging findings with the result of postmortem studies,” said Carter in an interview with SRF.

A POP Quiz
While other studies have looked at gamma band oscillations in schizophrenia, most of these have focused on evoked oscillations, those driven by a sensory stimulus or a task involving perceiving or tracking a stimulus (see SRF Current Hypothesis by Woo and colleagues). In the current study, first author Raymond Cho of the University of Pittsburgh and colleagues focused on induced gamma rhythms, which are driven not by any externally applied stimulus, but by tasks that call into play executive control processes of cognition. The authors used a cognitive task called the “preparing to overcome prepotency” task, or POP test, to address the question of whether gamma oscillations correlate with cognitive control in schizophrenia. In this test, volunteers were shown a fleeting green or red square followed one second later by an arrow. When the arrow followed the green prompt, the volunteer had to respond by clicking a button with the same hand (right arrow, right hand), but if the arrow followed the red prompt, then the volunteer was required to respond with the opposite hand (right arrow, left hand), a scenario that requires more cognitive control. The researchers specifically chose this task because it is well-known to activate the DLPFC and because that activation correlates well with performance in the task. The researchers found that schizophrenia patients had significantly more errors in the task that required high cognitive control, and that they also took significantly longer to respond in both high- and low-control cases.

To look for difference in gamma band oscillations that might correlate with the poorer performance, Cho and colleagues used a battery of electrodes to take EEG measurements. They found that in normal subjects, two electrodes, one in the right frontal region (electrode 2 or AF8, for those familiar with EEG nomenclature) and one in the left (electrode 21 or FC1), recorded significantly higher gamma band power differences between the high- and low-control tests; this difference was much lower in the schizophrenia patients, suggesting that they had more difficulty in mounting gamma band responses to the stimuli.

To try to understand the significance of these findings, Cho and colleagues correlated the gamma differences at these two electrodes with schizophrenia symptoms. They looked at disorganization—a classic symptom of the disease and which negatively correlates with activation of the DLPFC—and behavioral performance, also compromised in schizophrenia as demonstrated by the higher error rates in the cognitive test. The researchers found a positive correlation between the right frontal electrode measurements and disorganization, while the gamma oscillations detected by the left frontal electrode positively correlated with accuracy in the test.

The study shows that increased demand on cognitive control leads to increased gamma band oscillations in normal and schizophrenia patients, but that in two specific regions of the brain the patient response was poorer than control subjects. That the gamma oscillations in these left and right frontal regions also correlated with disorganization and accuracy, respectively, in the schizophrenia patients suggests that these particular regions of the brain may play distinct roles in the disease. As such, the study suggests several diagnostic, screening, and treatment approaches. “EEG assessment of prefrontal gamma synchrony, then, may provide a useful tool for assessing impairment of prefrontal cortical circuits in tandem with behavioral measures of cognitive control disturbances in schizophrenia,” write the authors.

In addition, because they are a lot easier and less invasive to do than MRI, EEGs could be used in large-scale studies of intermediary or endophenotypes, comparing these with, for example, genetic studies. And last, but not least, because the findings are consistent with predictions that others have made about the role of interneurons in schizophrenia, “some of the molecular targets that have been identified in those brain circuits now become treatment targets,” suggested Carter. These would include subsets of receptors and transporters for GABA, the major neurotransmitter involved in modulating gamma frequency oscillations (see SRF related news story).—Tom Fagan.

Schizophrenia is associated with dopaminergic dysfunction,...
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Schizophrenia is associated with dopaminergic dysfunction, impaired gamma synchronization and impaired methylation. It is therefore of interest that the D4 dopamine receptor is involved in gamma synchronization (Demiralp et al., 2006) and that the D4 dopamine receptor uniquely carries out methylation of membrane phospholipids (Sharma et al., 1999). A reasonable and unifying hypothesis would be that schizophrenia results from a failure of methylation to adequately support dopamine-stimulated phospholipid methylation, leading to impaired gamma synchronization. Synchronization in response to dopamine can provide a molecular mechanism for attention, as information in participating neural networks is able to bind together to create cognitive experience involving multiple brain regions.

Cho and colleagues find patients with schizophrenia showed...
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Cho and colleagues find patients with schizophrenia showed a reduction in induced gamma band activity in the dorsolateral prefrontal cortex compared to healthy control subjects during a behavioral task that is known to challenge cognitive control processes. Importantly, the induced gamma band activity was correlated with better performance in healthy subjects, and negatively correlated with higher disorganization symptoms in patients with schizophrenia. These findings help explain previous post-mortem evidence of disruptions in thalamofrontocortical circuits in these patients.

These findings tie together several different previously identified phenotypes into a unifying story. The ability to link phenotypes across translational research domains is paramount to understanding complex neuropsychiatric diseases like schizophrenia. Cho and colleagues provide an excellent example for connecting evidence from symptom rating scales with behavioral, neural systems and neurophysiological data. Although not specifically addressed by the authors, these data may have important implications for understanding the neural basis of thought disorder as well. Hopefully, these findings will provide a frame-work for examining more informed and specific phenotypes relevant to schizophrenia.